RU2146672C1 - Method of synthesis of 3-ethyl-5-methyl(±)2-[(2-aminoethoxy)- -methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridine- -dicarboxylate monobenzenesulfonate - Google Patents

Abstract

FIELD: organic chemistry, aminoheterocyclic compounds. SUBSTANCE: invention relates to the method of synthesis of the novel compound - 3-ethyl-5- -methyl(±)2-[(2-aminoethoxy)-methyl] -4-(2-chlorophenyl)-1,4- -dihydro-6-methyl-3,5-pyridinedicarboxylate monobenzenesulfo-nate. For synthesis of indicated compound 3-ethyl-5-methyl- -(6-8^oC)2-[(2-N-3-phenylmethylamino)-ethoxymethyl] -4-(2-chloro- -phenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate is mixed with hydrochloric acid solution in dioxane and stirred. Then benzenesulfoacid solution in acetone is added, stirred again, water is added, cooled and kept at 6-8 C for 8-12 h. EFFECT: simplified method, increased yield in technology of medicinal forms. 4 cl

Description

 The invention relates to the field of chemistry of heterocyclic compounds, as well as to the field of the pharmaceutical industry, specifically to a new method for producing 3-ethyl-5-methyl (±) 2 [(2-aminoethoxy) methyl] -4- (2-chlorophenyl) - 1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate of monobenzenesulfonate - amlodipine bezylate, which can be used in pharmacy.

 A known method of producing pharmaceutically acceptable salts of amlodipine (EP 0089167, C 07 D 211/90), in particular hydrochloride, sulfate, acetate, maleate. The disadvantage of the obtained salts is their low stability, which makes them unsuitable for the pharmaceutical industry.

 A known method of producing amlodipine besylate (USSR patent N1498388), as the most stable of the previously known salts of amlodipine. The disadvantage of this method is the complexity of the process, involving the allocation of amlodipine base in its pure form. An intermediate for the production of amlodipine besilate - amlodipine base is obtained from explosive azide compounds. As a result of a complex chemical synthesis scheme, a low yield of the final product is observed.

 Closest to the proposed invention is a method for producing amlodipine bezilate by reacting 3-ethyl-5-methyl (±) 2- [2- (N-triphenylmethylamino) ethoxymethyl] -4- (2-chlorophenyl) -1,4-dihydro 6-methyl-3,5-pyridinedicarboxylate (also known as tritylamodipine) with benzenesulfonic acid in a methanol or water-methanol medium when heated (RF patent N2105759). The disadvantage of this method is the low yield of the final product, the multi-stage process and the need for intense heating, which is undesirable for the final product and contributes to the formation of unstable high-energy impurities in it.

 Physical factors affect the stability of drugs, from the time they are received to to patients. The stability of the dosage form largely depends on the process that was used to obtain the starting substance. An important role belongs to the starting products of the synthesis, the selected solvents, and the purification of intermediate products.

 Stability largely depends on the chemical purity and physical properties of the drug substance. It is known that, depending on the crystallization conditions, the size of crystals, surface energy, and faceting can change. These physical properties affect the hygroscopicity, chemical activity, and therefore the stability of the drug. The shape and size of the crystals depend on the nature, degree of purity of the solvent, temperature conditions and the duration of the crystallization process, the presence of related substances. These factors influence, for example, the formation of polymorphic forms of substances of medicinal substances.

 The processes for obtaining the most stable modifications are described, for example, in RF patent N2120445, C 07 J 73/00; RF patent N2067093, C 07 C 303/44; RF patent N2051915, C 07 D 413/14; RF patent N2079489, C 07 C 259/06. As follows from these documents, the choice of solvent for the implementation of the task and crystallization conditions is a painstaking process in which the installation of a complex of all necessary parameters is largely a rare and successful find.

 The objective of the invention is to increase the yield of amlodipine besylate, suitable for use in the technology of dosage forms, while simplifying the method.

 The task is achieved by selecting a complex of reagents, solvents, as well as the conditions for the process of interaction of tritylamodipine and benzenesulfonic acid, which allow to obtain amlodipine besilate with a high yield and efficiency, suitable for further use in the pharmaceutical industry.

To obtain the final product according to the proposed invention, the following sequence of actions must be observed: tritylamodipine is added to the solution of hydrogen chloride in dioxane with stirring (the process is preferably carried out at a temperature of 20-24 ^o C); a solution of benzenesulfonic acid in acetone is added to the resulting mixture at the same temperature and stirred, excess water is added, it is slowly cooled, kept at a temperature of 6-8 ^o C for several hours, the precipitate formed is filtered off and washed with acetone, drying is carried out in vacuum at a temperature of 40 ^o C.

 The yield of amlodipine besylate is 89 ± 3%.

The invention is illustrated by the following example:
65 g (0.1 mol) of tritylamodipine is stirred in 300 ml of 2 N. a solution of hydrogen chloride in dioxane at a temperature of 23 ^o C for 3 hours. Then, 20 g (0.16 mol) of benzenesulfonic acid in 50 ml of acetone are added to the resulting mixture. The mixture is stirred for 30 minutes at a temperature of 23 ^° C. and 500 ml of water are added. After that, the reaction mixture was cooled to a temperature of 8 ^o C at a speed of 3 ^o C per hour and incubated for 10 hours. The precipitate was filtered off, washed on a filter with acetone (2 x 70 ml) and dried in vacuum at a temperature of 40 ^o C for 12 h

Obtain 49.3 g of a crystalline powder of amlodipine besylate with a melting point of 201.2 ^o C.

 The yield was 87%.

 When comparing amlodipine besilate obtained by the analogous method, by the prototype method and the proposed method, it was found that the final product obtained by the proposed method is less hygroscopic and is apparently a thermodynamically more stable modification. This clearly indicates that the amlodipine besilate obtained by the proposed method during storage and under the conditions of a rigid technological process (in the manufacture of drugs based on it, for example, tabletting) will not undergo changes in terms of the physical condition of the substance. This, in turn, will make it possible to obtain dosage forms having standard bioavailability in various series of the drug.

The resulting amlodipine besilate at a relative humidity of 95% and a temperature of 30 ^o C remains anhydrous for 7 days.

Claims (4)

1. The method of producing 3-ethyl-5-methyl (±) 2 [(2-aminoethoxy) methyl] -4- (2-chlorophenyl) -1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate monobenzenesulfonate by mixing 3-ethyl-5-methyl (±) 2- [2 (N-triphenylmethylamino) ethoxymethyl] -4- (2-chlorophenyl) -1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate with benzenesulfonic acid subsequent separation and purification of the target product, characterized in that 3-ethyl-5-methyl (±) 2- [2- (N-triphenylmethylamino) ethoxymethyl] -4- (2-chlorophenyl) -1,4-dihydro-6 methyl-3,5-pyridinedicarboxylate is mixed with a solution of hydrogen chloride in dioxane, stirred, add benzenesulfonic acid in acetone, re-mixed, add water, cooled and incubated for 8 to 12 hours at a temperature of 6 - 8 ^o C. 2. The method according to claim 1, characterized in that the cooling is carried out at a speed of 2 to 3 ^o C per hour. 3. The method according to PP.1 and 2, characterized in that the mixing is carried out at a temperature of 20-24 ^o C for 0.5 to 3.0 hours 4. The method according to PP.1 to 3, characterized in that the separation of the target product is carried out by filtration, and cleaning is carried out by washing with acetone on a filter, followed by drying in vacuum at a temperature of 37 - 42 ^o C for 9 to 12 hours